Others have shown that pristane induced arthritis (P.I.A.) in H-2k CBA mice can be inhibited by pre-immunizing mice with Mycobacterial (Mt) heat shock protein 65 (hsp 65) or with a synthetic immunodominant peptide 261-271 derived from Mt hsp 65 administered in Incomplete Freund's Adjuvants (IFA). We pre-immunized H-2d BALB/c.D2-Idh-Pep3 mice with Mt hsp 65 peptide 261-271 in IFA and found that pre-immunization prolongs the latent period and reduces the incidence of PCTs. The timing of immunization is critical. When the immunization is given 10 days before each pristane injection, suppression is observed. When given 60 days after the first pristane injection, PCT formation is dramatically accelerated. Our working hypothesis is that pre-immunization with peptides in IFA induces antigen specific T cell anergy and tolerance to those antigens. In contrast, post pristane immunization augments, by as yet undefined mechanisms, the immune responses to natural antigens. Clones of T cells so activated provide cognate interactions with B cells, driving them into plasma cell proliferation where additional oncogenic mutations are acquired. We are extensively developing this system to better define the specificity of the antigens involved and to determine how genetic susceptibility to PCT induction might be related to those autoimmune-related genetic and physiological mechanisms that suppress or augment clones of cells responding to natural antigens.